Background <p>This study aimed to investigate whether clinical syntax score (CSS) could predict in-hospital and long-term outcomes in patients with acute coronary syndrome (ACS) who underwent drug-eluting stent implantation following rotational atherectomy (RA).</p> Methods <p>A total of 179 patients with ACS who underwent drug-eluting stent implantation following RA were recruited. Angiographic parameters, age, creatinine, and left ventricular ejection fraction were used to calculate CSS in the enrolled patients. The patients were classified into low-CSS (<i>n</i> = 89) and high-CSS (<i>n</i> = 90) groups. Major adverse cardiac event (MACE) was defined as cardiac death, recurrent myocardial infarction, target vessel revascularization (TVR), and ischemic stroke. The predictive value of CSS for in-hospital and long-term outcomes was evaluated by the multivariable logistic and Cox analyses.</p> Results <p>Angiographic success was 97.8% in patients with ACS who underwent drug-eluting stent implantation following RA. In-hospital MACE was significantly higher in the high-CSS group than in the low-CSS group (21.11% vs. 6.74%), however, CSS was not independently associated with in-hospital MACE after multivariable adjustment. The Kaplan–Meier analysis revealed a significantly higher occurrence of all-cause death and MACE in the high-CSS group. The multivariate analysis showed that CSS was an independent predictor of MACE, cardiac death, and TVR at a mean follow-up of 3 years in patients with ACS who underwent RA.</p> Conclusions <p>CSS was not independently associated with in-hospital MACE. On the contrary, the CSS has predictive value for long-term major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) following drug-eluting stent implantation. However, this finding still requires further validation through large-scale studies with long-term follow-up in the future.</p>